Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study examined the pathophysiological role of parathyroid hormone-related protein (PTHrP) in humoral hypercalcaemia of malignancy (HHM). Seven human tumour xenografts were analysed in nude mice; five tumours (KEsC-2, oesophageal carcinoma; FA-6, pancreatic carcinoma; SEKI, melanoma; Lu-65A and Lu-61, lung carcinomas) were associated with hypercalcaemia and two tumours (MIA PaCa-2, pancreatic carcinoma; PLC/PRF/5, hepatocellular carcinoma) with normocalcaemia. Northern blot analyses, radioimmunoassay and bioassay confirmed the synthesis of PTHrP-like peptides by all five tumours associated with hypercalcaemia, but not by the two associated with normocalcaemia. These observations indicated a very close relationship between the production of PTHrP and the development of HHM. Gel filtration studies of three tumour tissue extracts revealed at least two different molecules with both PTHrP-like immunological and biological activities. One peak eluted at a position between PTHrP (1-141) and cytochrome C and the other at a position identical to cytochrome C. These results suggest that PTHrP molecules with a molecular size equal to or greater than cytochrome C participate as causative agents of HHM. All five tumour xenografts caused hypercalcaemia when grown to a size of 1.5 g in nude mice. Under cell culture conditions, four original cell lines, KEsC-2, FA-6, SEKI and Lu-65A secreted 450.0, 45.0, 3.6 and 3.0 pmol of immunoreactive PTHrP/1.5 x 10(9) cells (approximately equivalent to 1.5 g wet weight) 24 h-1 into their respective culture media. Since a subcutaneous infusion of 100 pmol 24 h-1 of PTHrP (1-34) into nude mice was sufficient to induce significant hypercalcaemia, we speculate that PTHrP alone released from tumour cells could induce hypercalcaemia at least in the case of KEsC-2, and possibly in FA-6. With regard to other tumours associated with hypercalcaemia, further examination of PTHrP and other compounds with bone-resorbing activity in these transplantable tumours is required to obtain a better understanding of this morbidity.
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PMID:Production of parathyroid hormone-related protein in tumour xenografts in nude mice presenting with hypercalcaemia. 199 2

We studied the effects on platelet function of cells isolated from freshly dissociated human tumor tissues (11 breast carcinomas, 9 colon carcinomas and 1 lymph node metastasis from melanoma) obtained at surgery as compared with cultured human tumor cells: namely, human melanoma 1402 cell line derived from a primary tumor and two lines derived from lymph node metastases (ME 7110/2 and Me 665/1) as well as a human hepatoma cell line (Hep G2). The three melanoma cell lines activated platelets by producing ADP, as evidenced by the inhibitory effect of apyrase and by the direct measurement of the agonist in the supernatants of tumor cell suspensions; this production was much greater by the cells derived from metastases than by the cells derived from the primary tumor. On the other hand, aggregation induced by Hep G2 hepatoma cells was unaffected by apyrase and was inhibited by hirudin or concanavalin A, suggesting that the cells aggregate platelets by producing thrombin, probably through tissue factor activity of the cells themselves. Cells isolated from 16 of the 21 human tumor tissues possessed a potent platelet-aggregating effect, which was not inhibited by apyrase, hirudin or concanavalin A, but was virtually abolished by the cysteine protease inhibitors iodoacetic acid or p-hydroxymercuri-phenylsulfonate. Collectively, our data demonstrate that cells isolated from freshly dissociated tumor tissues activate platelets through tumor-associated cysteine proteinases rather than by the ADP- or thrombin-dependent mechanisms characteristic of cultured human tumor cell lines.
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PMID:Mechanisms of platelet activation by cultured human cancer cells and cells freshly isolated from tumor tissues. 276 27

We report the functional and structural analysis of the 5' untranslated region (5'UTR) of human hepatoma HepG2 gamma-glutamyltransferase (GGT) mRNA. Transient expression of a hybrid GGT-luciferase gene in HepG2, MIA-Pa-Ca-2 and MG 63 cell lines shows that this 5'UTR acts as a tissue-specific translational enhancer. Evidence for transcripts with multiple 5'UTR coding for HepG2 GGT was obtained by RNase protection. Computer analysis of this 5'UTR detected the existence of a stable stem and loop structure containing multiple steroid modulatory elements.
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PMID:The 5' untranslated region of the human gamma-glutamyl transferase mRNA contains a tissue-specific active translational enhancer. 810 26

The aim of this study was to survey the expression of an embryonic cytokine gene, MK, in the normal organs and neoplastic tissues of adults. Northern analysis showed that MK mRNA was exclusively expressed in the kidney among murine organs including thymus, lung, heart, spleen, liver, and kidney. In situ hybridization analysis revealed that MK expression was localized in the proximal tubules and metaplastic Bowman's epithelium, but not in other nephron segments such as glomeruli, loop of Henle, distal tubules, and collecting ducts. To investigate whether MK expression is a marker of tubular cell lineage, several cell lines originating from renal tubules were tested. No expression of MK was detected in PtK1 and LLC-PK1 cells derived from marsupial and porcine proximal tubules or in MDBK and MDCK cells from bovine and canine distal/collecting tubules. Unexpectedly, the MK gene was expressed in a human renal cell carcinoma line, VMRC-RCW, and the expression was up-regulated in the presence of retinoic acid. To elucidate the involvement of MK in the development of tumors, we further examined its expression in a variety of human neoplastic cell lines: YMB-1-C (breast cancer), EBC-1 (lung squamous cell carcinoma), RERF-LC-OK (lung adenocarcinoma), SBC-3 (lung small cell carcinoma), HSC-2 (mouth squamous cell carcinoma), NUGC-2 (gastric cancer), COLO201 (colon cancer), HepG2 (hepatoma), MIA PaCa-2 (pancreatic cancer), MCAS (ovarian cancer), HeLa (cervical cancer), BeWo (chorionic carcinoma), ITO-II (testicular tumor), T24 (urinary bladder tumor), and G-401 (Wilms' tumor). Strong signals were detected in COLO201, HepG2, ITO-II, T24, G-401, and weaker but distinct signals were detected in YMB-1-C, HSC-2, and MCAS cells. The MK gene was, therefore, widely expressed in neoplastic cells originating from genital organs, intestinal tract, liver, mammary gland, and urinary tract, and the expression was not restricted to adenocarcinomas, but was also observed in other types of tumor cells. These findings suggest that a retinoic acid responsive gene, MK, may play a role in the pathophysiology of renal proximal tubules and tumorigenesis in many types of neoplasms.
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PMID:A retinoid responsive cytokine gene, MK, is preferentially expressed in the proximal tubules of the kidney and human tumor cell lines. 843 39

During the course of studies designed to identify the role of cytokines in the reprioritization of hepatic protein synthesis associated with cachexia we detected a hepatocyte-stimulating moiety in the supernatants of pancreatic cancer cells that was unrelated to interleukin (IL)-6. This study identifies that moiety as IL-8 and investigates the role of IL-8 in the induction of acute-phase protein production. The human pancreatic cancer cell line MIA PaCa-2 produced >1 ng/ml of IL-8 per 24 h, and supernatants from this cell line induced C-reactive protein (CRP) production from isolated human hepatocytes. Addition of neutralizing anti-human IL-8 antibody to such supernatants produced almost complete inhibition of CRP production. The addition of recombinant human IL-8 to hepatocytes resulted in a dose-dependent increase in CRP, alpha1-acid glycoprotein, and alpha1-antichymotrypsin production and a decrease in the production of transferrin and prealbumin. This study demonstrates that recombinant or tumor-derived IL-8 can modulate acute-phase protein production from isolated human hepatocytes and from human hepatoma cells.
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PMID:Interleukin-8 can mediate acute-phase protein production by isolated human hepatocytes. 935 1

We have established monoclonal antibodies from mice immunized with the human hepatocellular carcinoma cell line, hu-H2. One of the antibodies, designated 523(KY-3), was reactive with this hepatocellular carcinoma cell line as well as with the human pancreatic cancer cell line, MIA. Another monoclonal antibody, 512(KY-2), only reacted with the hepato-cellular carcinoma cell lines. Neither antibody reacted with the colon cancer cell line CW3. Pretreatment of peripheral blood mononuclear cells with 523 resulted in enhancement of their natural cytotoxicity to hu-H2 (9.0 vs 18.4% in subject 1, 3.5 vs 14.7% in subject 2, and 14.2 vs 31.0% in subject 3). In contrast, such antibody mediated enhanced natural cytotoxicity was not found by pretreatment of the same peripheral blood mononuclear cell with 512. With the similarity in reactivity of 523, this antibody dependent enhancement was found in natural cytotoxicity to hu-H2 and MIA but not to CW3. Based on the facts that 523 did not have a direct cytopathic effect on these tumours and that this 523-mediated enhanced natural cytotoxicity was inhibited by anti-FcgammaRIII antibody, we concluded that the 523-mediated enhanced cytotoxicity reflects its activity to induce antibody dependent cytotoxic cells. Thus, these results demonstrate that several distinct tumour-specific antigens exist in hepatocellular carcinoma (HCC) and that one of them represents a potentially useful target for immunotherapy of human hepatocellular carcinoma.
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PMID:Antibody dependent cell-mediated cytotoxicity using hepatocellular carcinoma reactive monoclonal antibody. 1022 14

The recently cloned organic cation transporter, OCTN2, isolated as a homologue of OCTN1, has been shown to be of physiological importance in the renal tubular reabsorption of filtered L-carnitine as a high-affinity Na+ carnitine transporter in man. Although the mutation of the OCTN2 gene has been proved to be directly related to primary carnitine deficiency, there is little information about the L-carnitine transport system in the liver. In this study, the characteristics of L-carnitine transport into hepatocytes were studied by use of cultured human hepatoma HLF cells, which expressed OCTN2 mRNA to a greater extent than OCTN1 mRNA. The uptake of L-carnitine into HLF cells was saturable and the Eadie-Hofstee plot showed two distinct components. The apparent Michaelis constant and the maximum transport rate were 6.59+/-1.85 microM (mean+/-s.d.) and 78.5+/-21.4 pmol/5 min/10(6) cells, respectively, for high-affinity uptake, and 590+/-134 microM and 1507+/-142 pmol/5 min/10(6) cells, respectively, for low-affinity uptake. The high affinity L-carnitine transporter was significantly inhibited by metabolic inhibitors (sodium azide, dinitrophenol, iodoacetic acid) and at low temperature (4 degrees C). Uptake of [3H]L-carnitine also required the presence of Na+ ions in the external medium. The uptake activity was highest at pH 7.4, and was significantly lower at acidic or basic pH. L-Carnitine analogues (D-carnitine, L-acetylcarnitine and gamma-butyrobetaine) strongly inhibited uptake of [3H] L-carnitine, whereas beta-alanine, glycine, choline, acetylcholine and an organic anion and cation had little or no inhibitory effect. In conclusion, L-carnitine is absorbed by hepatocytes from man by an active carrier-mediated transport system which is Na+-, energy- and pH-dependent and has properties very similar to those of the carnitine transporter OCTN2.
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PMID:Characteristics of L-carnitine transport in cultured human hepatoma HLF cells. 1050 33

The carbohydrate epitope, alphaGal epitope, is known as a major xenoantigen. The epitope exists abundantly in non-primate mammals and has recently been found on C-type retroviruses. Humans and Old World monkeys have anti-alphaGal antibody, a natural antibody. The present study was performed to examine if the alphaGal epitope could be used as a new target of gene therapy against human cancer. Bovine alpha1-3 galactosyltransferase (alpha1-3 GT) cDNA which produces the alphaGal epitope was electrophoretically transfected into the human pancreatic cancer cell line, MIA PaCa-2 and the human hepatocellular carcinoma cell line, huH7. The expression of the alphaGal epitope was confirmed by flow cytometry, using specific binding with IB4 lectin conjugated with fluorescein isothiocyanate. Transfected MIA PaCa-2 cells and huH7 cells showed a positive log shift for the alphaGal epitope. Next, we examined whether human cancer cells expressing the alphaGal epitope could be lysed by natural antibodies using the complement-dependent cytotoxic cross-match test. The results showed that transfected MIA PaCa-2 cells and huH7 cells were effectively lysed by human natural antibodies, and the killing was observed with any serum irrelevant of blood type. The results indicate that transfection of the functional alpha1-3 GT gene into human cancer cells can lead to their transformation, making them susceptible to lysis by natural antibodies, and, thus, useful for gene therapy.
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PMID:Expression of xenoantigen transformed human cancer cells to be susceptible to antibody-mediated cell killing. 1117 30

The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to death. With new discoveries in cancer biology, the pathological and biological prognostic factors of HCC have been studied quite extensively. Analyzing molecular markers (biomarkers) with prognostic significance is a complementary method. A large number of molecular factors have been shown to associate with the invasiveness of HCC, and have potential prognostic significance. One important aspect is the analysis of molecular markers for the cellular malignancy phenotype. These include alterations in DNA ploidy, cellular proliferation markers (PCNA, Ki-67, Mcm2, MIB1, MIA, and CSE1L/CAS protein), nuclear morphology, the p53 gene and its related molecule MD M2, other cell cycle regulators (cyclin A, cyclin D, cyclin E, cdc2, p27, p73), oncogenes and their receptors (such as ras, c-myc, c-fms, HGF, c-met, and erb-B receptor family members), apoptosis related factors (Fas and FasL), as well as telomerase activity. Another important aspect is the analysis of molecular markers involved in the process of cancer invasion and metastasis. Adhesion molecules (E-cadherin, catenins, serum intercellular adhesion molecule-1, CD44 variants), proteinases involved in the degradation of extracellular matrix (MMP-2, MMP-9, uPA, uPAR, PAI), as well as other molecules have been regarded as biomarkers for the malignant phenotype of HCC, and are related to prognosis and therapeutic outcomes. Tumor angiogenesis is critical to both the growth and metastasis of cancers including HCC, and has drawn much attention in recent years. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), thrombospondin (TSP), angiogenin, pleiotrophin, and endostatin (ES) levels, as well as intratumor microvessel density (MVD) have been evaluated and found to be of prognostic significance. Body fluid (particularly blood and urinary) testing for biomarkers is easily accessible and useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum, and its genetic alterations in HCC are other important trends. More attention should be paid to these two areas in future. As the progress of the human genome project advances, so does a clearer understanding of tumor biology, and more and more new prognostic markers with high sensitivity and specificity will be found and used in clinical assays. However, the combination of some items, i.e., the pathological features and some biomarkers mentioned above, seems to be more practical for now.
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PMID:The prognostic molecular markers in hepatocellular carcinoma. 1204 56

Hepatocellular carcinoma (HCC) and pancreatic cancer are at the forefront of chemotherapy-resistant tumors with poor prognosis. Even with innovative treatment regimens, response rates remain low and the duration of response is short. We examined whether the suppression of DNA methylation was capable of enhancing the sensitivity of hepatoma and pancreatic cancer cell lines to 5-fluorouracil (5-FU). 5-aza-2'-deoxycytidine (5-aza-dC) at 2 microM, a specific DNA methylation inhibitor, did not induce cell death in Huh-7 with or without HCV, HLE, HepG2 and MIA PaCa-2 cells. However, a combination of 5-aza-dC with 5-FU showed a reduction in cell viability and induction of apoptosis in these cell lines to a greater degree than with 5-FU only. These findings underline the fact that DNA methylation plays a key role in conferring chemoresistance to hepatoma and pancreatic cancer, and the combination of DNA methylation inhibitor with chemotherapy could be a novel and highly effective tool for future targeted therapy of chemoresistant tumors.
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PMID:5-aza-2'-deoxycytidine sensitizes hepatoma and pancreatic cancer cell lines. 1614 60


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